Production of pantetheine and pantethine



Patented June 8, 1954 l g P ODUCTIO OF PANTETHEINE-AND lANTETHINEEsmond,E..Snell, Austin, Tex., and Eugene L.

Wittle and James A. Moore, Detroit, Mich.,,assignors to-Barke, Davis &Company, Detroit; Mich., a corporation of Michigan No Drawing.Applicationqseptember 18,1952; Serial No. 310,362;

7 Claims. (Cl. 260561) This -;application is a continuation-impart ofThe bis[N' (fi-alanyl) -2-aminoethyl]disul-fide ourcopending applicationSerial Number 191,936, and N-(p-alanyl) -2-aminoethyl mercaptanstartfiled October 24, 1950, and the-invention relates ing materialscanbeused in either the free base to-a process for the production oforganicsulfur or acid addition salt form. When an acid addi- ;compounds.I More particularly, the invention 5 tionsalt is used an equivalentamount of an relates to a process for the production of bis [N- alkalinematerial such as an alkali or alkaline pantothenyl-z-aninoethylldisulfide(pantearth metal hydroxide or alcoholate is added toethine) and- :N- (+)-pantothenyle2-aminoethyl the reaction mixture toliberate the free amine mercaptan (pantetheine). in situ.

In accordance with the invention, pantethine The products produced bythe process of the and; pantetheine; are produced by condensing presentinvention, that is, pantethine and pante- -pantolactonewith bis[N(,o-alanyl)-2- theine, are growth factors for microorganismsaminoethylldisuliideand N-(fi-alanyl)-2+aminoof the Lactobacillus genusand are capable of ,ethylmercaptan, respectively. Thetransformacorrecting pantothenic acid deficiencies in ani- ,tio nsinvolved can-be represented diagrammatimals. cal ly asiollowsq Thep-thioethyl amide of fi-alanine and the on; OH zcm- HC=O [NHz-OHgCH-CNHCHzCHz-S]a 1 n n [OHaOBI-r-EL-OHOH-Q+NH+CHQCHzCNH-CHnCHn-S-h CH:Pantethine CH; CH H GHQ- -cnc=o +NHicIncH -cNH-0HcH=-sH (13B; u u CH:QH;(|CHO,HO+NH- CHlQBF QTNHfCHQQHZ SH Pantetbeine The condensation can becarried out in the corresponding disulfide used as starting materialspresence or absence of a solvent. As solvents, can be prepared inseveral ways. For instance,

Water, lower aliphatic alcohols, hydrocarbons, they may be prepared bycondensing ethyl carlower aliphatic ethers and mixtures of the samebobenzoxy-p-alanate or carbobenzoxy-fl-alanyl can be used. Best resultsare obtained using chloride with p-mercaptoethylamine orbisqflsubstantially anhydrous lower aliphatic alcohols et y u fi e andtreating the reaction as solvents and a reaction temperature of to p oct With phosphonium iodide to split Off the C, carbobenzoxy group. Thesestarting materials can The relative quantities of the two reactants arealso be prepared by treating N-(N-carbobenzoxynot particularly critical,but in most instances fi-alanyD-Z-aminoethanol with phosphorus penit ispreferable to use a slight excess of the tasulficle and then splittingofi the carbobenzoxy pantolactone. When the reaction is carried outgroup by treatment with phosphonium iodide. withbis-(N-(fi-alanyl)-2-aminoethyl)disulfide at The p-thioethyl amide offi-alanine so obtained least two equivalents of the -pantolactone arecan be converted to the disulfide by oxidation with used for eachequivalent of the disulfide while air, hydrogen peroxide or iodine.Alternatively, only one equivalent of the ()-pantolactone is themercaptan can be oxidized before the carborequired per equivalent ofmercaptan when carbenzoxy group is split ofi. rying out the process withN-(fi-alanyD-2-amino- The invention is illustrated by the followingethyl mercaptan. examples.

Example 1 10.2 cc. of 0.98 N sodium methoxide in methanol is added to1.84 g. of bislN-(-alanyD-2- aminoethyl] disulfide dihydrochloride in 15cc. of methanol, the mixture diluted with an equal volume of ether andthe sodium chloride removed by filtration. The solvents are evaporatedfrom the filtrate and 1.3 g. of -pantolactone added to the residualbis[N-( 3-alanyl)-2-aminoethylldisulfide. The mixture is heated at 60 C.for one hour, cooled and dissolved in 1.5 cc. of methanol. The solutionis diluted with 100 cc. of anhydrous ether and the oil which separatescollected. The oil is again dissolved in methanol and precipitated withether and then placed under vacuo in a vacuum desiccator. The tanhydroscopic solid, 1.1 g., so obtained is practically pure pantethine[bis(N pantothenyl 2-aminoethyl)disulfide] Example 2 Example 3 4.1 cc.of a 0.98 N solution of sodium methylate in methanol is added to amixture consisting of 912 mg. of bisEN-(fi-alanyl) -2-aminoethylldisulfide dihydrobromide and 500 mg. of (--)-pantolactone in 20 cc. ofmethanol. The reaction mixture is allowed to stand at 25 C. forforty-eight hours and then heated to boiling for five minutes. Thesolvents are evaporated in vacuo and the residual pantethine purified asdescribed in Example 1.

Example 4 A mixture consisting of 164 mg. of N-(B-alanyl)-2aminoethylmercaptan and 144 mg. of

()-pantolactone in 1.8 cc. of methanol is allowed to stand at 25 C. fortwenty-four hours and then heated to 50 C. for one-half hour. Thesolution is evaporated to dryness in a current of nitrogen to obtain 200mg. of pantetheine as a clear oil. The product so obtained is 15% pureby microbiological assay.

What we claim is:

1. Process for the production of a compound of the class consisting ofbis[N-(+)-pantothenyl-2-aminoethyll-disulfide andN-(+)-pantothenyl-Z-aminoethyl mercaptan which comprises condensingrespectively a member of the class consisting of bis- [N- (B-alanyl)-2-aminoethyl]di sulfide and N-(p-alanyD-Z-aminoethyl mercaptan with-pantolactone.

2. Processfcr the production of bis-[N-(+)- pantothenyl-2-aminoethylldisulfide which comprises condensing bisEN-(p-alanyl)-2-aminoethylldisulfide with at least two equivalents of pantolactone.

3. Process for the production of bis[N-(+)-pantothenyl-Z-aminoethylldisulfide which comprises condensing bisEN-(p-alanyl) -2-aminoethylldisulfide with at least two equivalents ofpantolactone in an anhydrous lower aliphatic alcohol at a temperaturebetween 20 and C.

4. Process for the production of N-(+) -pantothenyl-2-aminoethylmercaptan which comprises condensing N- (fi-alanyl) -2-aminoethylmercaptan with -pantolactone.

5. Process for the production of N(+) -panto'- thenyl-Z-aminoethylmercaptan which comprises condensing N-(fi-alanyl) -2-aminoethylmercaptan with -pantolactone in an anhydrous lower aliphatic alcohol ata temperature between 20 and 100 C. 1

6. Process of claim 2 in which bis-[N(+)pantothenyl-2-aminoethyl]disulfide is provided in situ by adding anequivalent of an alkaline alcoholate to an acid addition salt thereof.-

7. Process of claim 4 in which N-(p-alanyl) -2- aminoethyl mercaptan isprovided insitu by adding an equivalent of an alkaline alcoholate to anacid addition salt thereof.

References Cited in the file of this patent? UNITED STATES PATENTSNumber Name Date 2,377,105 Reichstein May 29, 1945 2,413,077 SchniderDec. 24, 1946 FOREIGN PATENTS Number Country 'Date 568,355 Great BritainMar. 30, 1945 943,459 France Oct. 4, 1948 OTHER REFERENCES Barnett: J.Chem. Soc. (London), 1944, pp. 5 t0 8.

1. PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE CLASS CONSISTING OFBIS(N-(+)-PANTOTHENYL-2-AMINOETHYL)-DISULFIDE ANDN-(+)-PANTOTHENYL-2-AMINOETHYL MERCAPTAN WHICH COMPRISES CONDENSINGRESPECTIVELY A MEMBER OF THE CLASS CONSISTING OFBIS-(N-(B-ALANYL)-2-AMINOETHYL)DISULFIDE AND N-(B-ALANYL)-2-AMINOETHYLMERCAPTAN WITH (-)-PANTOLACTONE.